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1.
Mol Genet Genomic Med ; 8(9): e1370, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32573962

RESUMO

BACKGROUND: Galectin-3 plays a crucial role in the regulation of inflammation. The aim of this study was to elucidate the association between LGALS3 genotypes, galectin-3 levels, and inflammatory marker levels in patients with coronary artery disease (CAD). RESULTS: A total of 474 patients with CAD were enrolled. Significant correlations were discerned between galectin-3 levels and leukocyte counts, C-reactive protein, soluble intercellular adhesion molecule-1, and matrix metalloproteinase 9 levels (all p < .05). The LGALS3 rs2274273, rs4644, rs4652 genotypes, and haplotypes CAC, CCC, and ACT exhibited a significant association with galectin-3 levels (for genotypes, p = 1.05 × 10-25 , 3.54 × 10-25 , and 2.74 × 10-7 , respectively). Multivariate analysis showed LGALS3 rs2274273 and rs4644 genotypes contributing to 20.8% variation of galectin-3 levels. However, there was no association between LGALS3 genotypes and other inflammatory marker levels. CONCLUSIONS: Our data showed strong genetic determinants of galectin-3 levels in patients with CAD. The galectin-3 levels, but not LGALS3 genotypes, were associated with multiple inflammatory marker levels. Further study may be necessary to elucidate the molecular mechanism of galectin-3 in the pathogenesis of chronic inflammatory disorders.


Assuntos
Proteínas Sanguíneas/genética , Doença da Artéria Coronariana/genética , Galectinas/genética , Polimorfismo de Nucleotídeo Único , Idoso , Proteína C-Reativa/análise , Doença da Artéria Coronariana/sangue , Feminino , Galectinas/sangue , Humanos , Molécula 1 de Adesão Intercelular/sangue , Contagem de Leucócitos , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade
2.
Biomark Med ; 13(9): 751-760, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31157557

RESUMO

Aim: This study aims to investigate whether osteoprotegerin (OPG) or osteopontin (OPN) single nucleotide polymorphisms (SNPs) will predict survival. Materials & methods: This study enrolled 617 participants undergoing health examination, 536 coronary artery disease (CAD) patients and 86 peripheral artery disease (PAD) patients. Genotypes of OPG SNP rs2073618 and OPN SNP rs11730582 were determined. OPG and OPN levels were measured. Results: In both CAD and PAD populations, high OPG and OPN levels were strong predictors of all-cause death. The OPG rs2073618 CC genotype and the OPN rs11730582 TT genotype did not predict mortality. Conclusion: High OPG and high OPN levels, but not OPG rs2073618 CC genotype or OPN rs11730582 TT genotype, were strong predictors of mortality in both CAD and PAD patients.


Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Osteopontina/sangue , Osteopontina/genética , Osteoprotegerina/sangue , Osteoprotegerina/genética , Doença Arterial Periférica/sangue , Doença Arterial Periférica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Doença da Artéria Coronariana/mortalidade , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/mortalidade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Taiwan/epidemiologia
3.
Nat Genet ; 49(10): 1450-1457, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28869590

RESUMO

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.


Assuntos
Doença das Coronárias/genética , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Ásia/epidemiologia , Povo Asiático/genética , Biomarcadores , Comorbidade , Doença das Coronárias/epidemiologia , Doença das Coronárias/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Europa (Continente)/epidemiologia , Loci Gênicos/genética , Predisposição Genética para Doença , Cadeias HLA-DRB5/genética , Humanos , Redes e Vias Metabólicas/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Terapia de Alvo Molecular , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genética
4.
Circ Res ; 121(1): 81-88, 2017 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-28506971

RESUMO

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/genética , Doença das Coronárias/diagnóstico , Doença das Coronárias/genética , Variação Genética/genética , Adulto , Idoso , Estudos de Casos e Controles , Proteínas de Transferência de Ésteres de Colesterol/sangue , Doença das Coronárias/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
5.
Hum Genet ; 136(6): 771-800, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28391526

RESUMO

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.


Assuntos
Índice de Massa Corporal , Etnicidade/genética , Genética Populacional , Humanos , Obesidade/epidemiologia , Obesidade/genética
6.
Hum Mol Genet ; 25(24): 5500-5512, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-28426890

RESUMO

Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.


Assuntos
HDL-Colesterol/genética , LDL-Colesterol/genética , Estudo de Associação Genômica Ampla , Lipídeos/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Negro ou Afro-Americano/genética , Apolipoproteína A-V/genética , Povo Asiático/genética , Feminino , Hispânico ou Latino/genética , Humanos , Indígenas Norte-Americanos/genética , Lipase Lipoproteica/genética , Masculino , Triglicerídeos/genética
7.
Diabetologia ; 56(12): 2619-28, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24013783

RESUMO

AIMS/HYPOTHESIS: Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population. METHODS: A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression. RESULTS: We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1. CONCLUSIONS/INTERPRETATION: These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.


Assuntos
Povo Asiático/genética , Quinase 5 Dependente de Ciclina/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Idoso , Glicemia/metabolismo , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Insulina/sangue , Masculino , tRNA Metiltransferases
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